Regulation of proto-oncogenes and salivary gland cell proliferation.

The proto-oncogenes c-fos and c-jun express proteins targeted into the nucleus. The fos and jun proteins form a heterodimeric complex that binds to regulatory elements in the promoter region of specific genes to influence their transcription. Through such a mechanism, the fos and jun proteins have been suggested to link extracellular stimuli to short- and long-term functional changes in cells. Recently we have shown that beta-adrenergic receptor stimulation of rat parotid acinar cells in vitro or addition of 8-BrcAMP in a rat submandibular cell line (RSMT-A5) increases the expression of the c-fos gene in a time-dependent manner. Maximal responses were found at 60 min. The expression of the c-fos gene did not correlate with DNA synthesis in either cell type, and c-fos transcripts were undetectable in the glands of animals treated for eight days with isoproterenol. The new data presented here extended our observations to c-jun gene expression in both salivary cell types where a similar pattern of expression for this proto-oncogene was seen. Conversely, treatment of rats with isoproterenol for nine days resulted in the appearance of two c-abl mRNAs of unique size, in addition to the known 5.3-kb c-abl transcripts. The data suggest that beta-adrenergic receptor stimulation or exposure to 8-BrcAMP induces the early expression of the "nuclear proto-oncogenes" c-fos and c-jun before changes are noted in salivary epithelial cell proliferation. Differences in c-abl mRNA size, occurring later, may be associated with the morphological and biochemical changes known to occur in rat parotid glands after chronic beta-adrenoreceptor stimulation.